The Chemistry Core will synthesize novel molecular probes for biological studies on cocaine addiction that will be available for the various projects and pilot projects within the Center. These molecular probes will enable the Center to explore central questions regarding cocaine addiction. "Chemical knockouts" blocking the monoamine transporters will be generated and used to study cocaine sensitization. Selective serotonin transporter (SERT) inhibitors will be used to study the role of the SERT inhibition on cocaine addiction. New neuroimaging agents will be generated to study dopamine transporter (DAT) and SERT neurochemical changes in the brain. Differentially functionalized radiolabeled irreversible ligands will be prepared to study the binding sites of DAT inhibitors. The Chemistry Core will interact with virtually all the other projects in the Center. Interaction with subproject 0001 (Childers) will be very extensive because a major component of subproject 0001 will be the use ol radiolabeled irreversible inhibitors to map the DAT. Promising irreversible inhibitors will also be evaluated behaviorally in subproject 0005 (Smith/Martin). Subproject 0008 (Vrana) will be exploring the effects of long acting tropanes on specific gene expression, with emphasis on connexins. One component of subproject 0011 (Roberts) will be the exploration of how the chronisity of cocaine administration impacts regional effects and connexin proteins in the brain. Long acting tropanes will be useful molecular tools for this project. Precursors to PEr radioligands will be prepared for the PET Imaging Core and these will be used in subProject 0012 (Porrino) and 0009 (Nader). The development of new radioligands is proposed in collaborative studies involving the Pilot Projects. A major component of Project 7 is to investigate the ability of compounds from the Chemistry Core with selectivity for SERT to selectively decrease cocaine self-administration in rhesus monkeys.